tbuckley/cabot-search huggingface dataset:
ChAdOx1 nCoV-19 (AZD1222) vaccine-induced Fc receptor binding tracks with differential susceptibility to COVID-19
Authors: Paulina Kaplonek, Deniz Cizmeci, Gaurav Kwatra, Alane Izu, Jessica Shih-Lu Lee, Harry L. Bertera, Stephanie Fischinger, Colin Mann, Fatima Amanat, Wenjun Wang, Anthonet L. Koen, Lee Fairlie, Clare L. Cutland, Khatija Ahmed, Keertan Dheda, Shaun L. Barnabas, Qasim Ebrahim Bhorat, Carmen Briner, Florian Krammer, Erica Ollman Saphire, Sarah C. Gilbert, Teresa Lambe, Andrew J. Pollard, Marta Nunes, Manfred Wuhrer, Douglas A. Lauffenburger, Shabir A. Madhi, Galit Alter
Journal: Nature Immunology (2023)

Abstract Despite the success of COVID-19 vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged that can cause breakthrough infections. Although protection against severe disease has been largely preserved, the immunological mediators of protection in humans remain undefined. We performed a substudy on the ChAdOx1 nCoV-19 (AZD1222) vaccinees enrolled in a South African clinical trial. At peak immunogenicity, before infection, no differences were observed in immunoglobulin (Ig)G1-binding antibody titers; however, the vaccine induced different Fc-receptor-binding antibodies across groups. Vaccinees who resisted COVID-19 exclusively mounted FcγR3B-binding antibodies. In contrast, enhanced IgA and IgG3, linked to enriched FcγR2B binding, was observed in individuals who experienced breakthrough. Antibodies unable to bind to FcγR3B led to immune complex clearance and resulted in inflammatory cascades. Differential antibody binding to FcγR3B was linked to Fc-glycosylation differences in SARS-CoV-2-specific antibodies. These data potentially point to specific FcγR3B-mediated antibody functional profiles as critical markers of immunity against COVID-19.
Increased Ca <sup>2+</sup> Transient Underlies RyR2-Related Left Ventricular Noncompaction
Authors: Mingke Ni, Yanhui Li, Jinhong Wei, Zhenpeng Song, Hui Wang, Jinjing Yao, Yong-Xiang Chen, Darrell Belke, John Paul Estillore, Ruiwu Wang, Alexander Vallmitjana, Raul Benitez, Leif Hove-Madsen, Wei Feng, Ju Chen, Thomas M. Roston, Shubhayan Sanatani, Anna Lehman, S.R. Wayne Chen
Journal: Circulation Research (2023)

A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/-, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M+/- loss-of-function mutation on cardiac structure and function.We generated a mouse model expressing the CRDS-LVNC-associated RyR2-I4855M+/- mutation. Histological analysis, echocardiography, ECG recording, and intact heart Ca2+ imaging were performed to characterize the structural and functional consequences of the RyR2-I4855M+/- mutation.As in humans, RyR2-I4855M+/- mice displayed LVNC characterized by cardiac hypertrabeculation and noncompaction. RyR2-I4855M+/- mice were highly susceptible to electrical stimulation-induced ventricular arrhythmias but protected from stress-induced ventricular arrhythmias. Unexpectedly, the RyR2-I4855M+/- mutation increased the peak Ca2+ transient but did not alter the L-type Ca2+ current, suggesting an increase in Ca2+-induced Ca2+ release gain. The RyR2-I4855M+/- mutation abolished sarcoplasmic reticulum store overload-induced Ca2+ release or Ca2+ leak, elevated sarcoplasmic reticulum Ca2+ load, prolonged Ca2+ transient decay, and elevated end-diastolic Ca2+ level upon rapid pacing. Immunoblotting revealed increased level of phosphorylated CaMKII (Ca2+-calmodulin dependent protein kinases II) but unchanged levels of CaMKII, calcineurin, and other Ca2+ handling proteins in the RyR2-I4855M+/- mutant compared with wild type.The RyR2-I4855M+/- mutant mice represent the first RyR2-associated LVNC animal model that recapitulates the CRDS-LVNC overlapping phenotype in humans. The RyR2-I4855M+/- mutation increases the peak Ca2+ transient by increasing the Ca2+-induced Ca2+ release gain and the end-diastolic Ca2+ level by prolonging Ca2+ transient decay. Our data suggest that the increased peak-systolic and end-diastolic Ca2+ levels may underlie RyR2-associated LVNC.
Eligibility for vericiguat in a real‐world heart failure population according to trial, guideline and label criteria: Data from the Swedish Heart Failure Registry
Authors: Ngoc V. Nguyen, Felix Lindberg, Lina Benson, Giulia Ferrannini, Egidio Imbalzano, Peter G.M. Mol, Ulf Dahlström, Giuseppe M.C. Rosano, Justin Ezekowitz, Javed Butler, Lars H. Lund, Gianluigi Savarese
Journal: European Journal of Heart Failure (2023)

We investigated the eligibility for vericiguat in a real-world heart failure (HF) population based on trial, guideline and label criteria.From the Swedish HF registry, 23 573 patients with HF with reduced ejection fraction (HFrEF) enrolled between 2000 and 2018, with a HF duration ≥6 months, were considered. Eligibility for vericiguat was calculated based on criteria from (i) the Vericiguat Global Study in Subjects with Heart Failure and Reduced Ejection Fraction (VICTORIA) trial; (ii) European and American guidelines on HF; (iii) product labelling according to the Food and Drug Administration and European Medicines Agency. Estimated eligibility for vericiguat in the trial, guidelines, and label scenarios was 21.4%, 47.4%, and 47.4%, respectively. Prior HF hospitalization within 6 months was the criterion limiting eligibility the most in all scenarios (met by 49.1% of the population). In the trial scenario, other criteria meaningfully limiting eligibility were elevated N-terminal pro-B-type natriuretic peptide levels and nitrate use. In all scenarios, eligibility was higher among patients hospitalized for HF at baseline (44.3% vs. 21.4% [trial scenario] and 97.3% vs. 47.4% [guideline/label scenarios] for hospitalized vs. non-hospitalized patients). Overall, eligible patients were older, had more severe HF, more comorbidities, and consequently higher cardiovascular mortality and HF hospitalization rates compared with ineligible patients across all scenarios.In a large and contemporary real-world HFrEF cohort, we estimated that 21.4% of patients would be eligible for vericiguat according to the VICTORIA trial selection criteria, 47.4% based on guidelines and labelling. Eligibility for vericiguat translated into the selection of a population at high risk of morbidity/mortality.
Association of Open Reduction and Internal Fixation With Volar Locking Plate for Distal Radius Fractures With Patient-Reported Outcomes in Older Adults
Authors: Mayank Jayaram, Shannon M. Wood, Robert L. Kane, Lan-Yan Yang, Kevin C. Chung
Journal: JAMA Network Open (2023)

Importance Randomized clinical trials (RCTs) and meta-analyses have reported inconsistent conclusions regarding optimal distal radius fracture (DRF) treatment in older adults and are limited due to the inclusion of cohort studies with small sample sizes. A network meta-analysis (NMA) addresses these limitations by only synthesizing direct and indirect evidence from RCTs and may clarify optimal DRF treatment in older adults. Objective To examine DRF treatment results in optimal short-term and intermediate-term patient-reported outcomes. Data Sources Searches of MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trials were conducted for RCTs that investigated DRF treatment outcomes in older adults between January 1, 2000, and January 1, 2022. Study Selection Randomized clinical trials including patients with a mean age of 50 years or older that compared the following DRF treatments were eligible for inclusion: casting, open reduction and internal fixation with volar lock plating (ORIF), external fixation, percutaneous pinning, and nail fixation. Data Extraction and Synthesis Two reviewers independently completed all data extraction. An NMA aggregated all direct and indirect evidence among DRF treatments. Treatments were ranked by surface under the cumulative ranking curve score. Data are reported as standard mean differences (SMDs) and 95% CIs. Main Outcomes and Measures The primary outcome was short-term (≤3 months) and intermediate-term (&amp;amp;gt;3 months to 1 year) Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire scores. Secondary outcomes included Patient-Rated Wrist Evaluation (PRWE) scores and 1-year complication rates. Results In this NMA, 23 RCTs consisting of 3054 participants (2495 women [81.7%]) with a mean (SD) age of 66 (7.8) years were included. At 3 months, DASH scores were significantly lower for nail fixation (SMD, −18.28; 95% CI, −29.93 to −6.63) and ORIF (SMD, −9.28; 95% CI, −13.90 to −4.66) compared with casting. The PRWE scores were also significantly lower for ORIF (SMD, −9.55; 95% CI, −15.31 to −3.79) at 3 months. In the intermediate term, ORIF was associated with lowered DASH (SMD, −3.35; 95% CI, −5.90 to −0.80) and PRWE (SMD, −2.90; 95% CI, −4.86 to −0.94) scores. One-year complication rates were comparable among all treatments. Conclusions and Relevance The findings of this NMA suggest that ORIF may be associated with clinically significant improvements in short-term recovery compared with casting for multiple patient-reported outcomes measures with no increase in 1-year complication rates. Shared decision-making with patients may be useful to identify patient preferences regarding recovery to determine optimal treatment.
A complete telomere-to-telomere assembly of the maize genome
Authors: Jian Chen, Zijian Wang, Kaiwen Tan, Wei Huang, Junpeng Shi, Tong Li, Jiang Hu, Kai Wang, Chao Wang, Beibei Xin, Haiming Zhao, Weibin Song, Matthew B. Hufford, James C. Schnable, Weiwei Jin, Jinsheng Lai
Journal: Nature Genetics (2023)

Abstract A complete telomere-to-telomere (T2T) finished genome has been the long pursuit of genomic research. Through generating deep coverage ultralong Oxford Nanopore Technology (ONT) and PacBio HiFi reads, we report here a complete genome assembly of maize with each chromosome entirely traversed in a single contig. The 2,178.6 Mb T2T Mo17 genome with a base accuracy of over 99.99% unveiled the structural features of all repetitive regions of the genome. There were several super-long simple-sequence-repeat arrays having consecutive thymine–adenine–guanine (TAG) tri-nucleotide repeats up to 235 kb. The assembly of the entire nucleolar organizer region of the 26.8 Mb array with 2,974 45S rDNA copies revealed the enormously complex patterns of rDNA duplications and transposon insertions. Additionally, complete assemblies of all ten centromeres enabled us to precisely dissect the repeat compositions of both CentC-rich and CentC-poor centromeres. The complete Mo17 genome represents a major step forward in understanding the complexity of the highly recalcitrant repetitive regions of higher plant genomes.
Implication of the Global Initiative for Chronic Obstructive Lung Disease 2023 report for resource-limited settings: tracing the G in the GOLD
Authors: Bruce J. Kirenga, Patricia Alupo, Frederik van Gemert, Rupert Jones
Journal: European Respiratory Journal (2023)

<b>COPD guidelines still have blind spots for low-resource settings. If GOLD is truly to be considered a global report on COPD, more attention will need to be paid to practical solutions in global settings.</b> https://bit.ly/3zusjOd
Periodontitis as a promoting factor of T2D: current evidence and mechanisms
Authors: Yuan Su, Leilei Ye, Chen Hu, Yanli Zhang, Jia Liu, Longquan Shao
Journal: International Journal of Oral Science (2023)

Abstract Periodontitis is an infectious disease caused by an imbalance between the local microbiota and host immune response. Epidemiologically, periodontitis is closely related to the occurrence, development, and poor prognosis of T2D and is recognized as a potential risk factor for T2D. In recent years, increasing attention has been given to the role of the virulence factors produced by disorders of the subgingival microbiota in the pathological mechanism of T2D, including islet β-cell dysfunction and insulin resistance (IR). However, the related mechanisms have not been well summarized. This review highlights periodontitis-derived virulence factors, reviews how these stimuli directly or indirectly regulate islet β-cell dysfunction. The mechanisms by which IR is induced in insulin-targeting tissues (the liver, visceral adipose tissue, and skeletal muscle) are explained, clarifying the influence of periodontitis on the occurrence and development of T2D. In addition, the positive effects of periodontal therapy on T2D are overviewed. Finally, the limitations and prospects of the current research are discussed. In summary, periodontitis is worthy of attention as a promoting factor of T2D. Understanding on the effect of disseminated periodontitis-derived virulence factors on the T2D-related tissues and cells may provide new treatment options for reducing the risk of T2D associated with periodontitis.
Hypoxia-Responsive lncRNA AC115619 Encodes a Micropeptide That Suppresses m6A Modifications and Hepatocellular Carcinoma Progression
Authors: Qiangnu Zhang, Teng Wei, Lesen Yan, Siqi Zhu, Wen Jin, Yu Bai, Yuandi Zeng, XiaoFei Zhang, Zexin Yin, Jilin Yang, Wenjian Zhang, Meilong Wu, Yusen Zhang, Liping Liu
Journal: Cancer Research (2023)

Long noncoding RNAs (lncRNA) regulate a number of aspects of cancer biology. Recent research has shown that lncRNAs can encode micropeptides that mediate their functions in tumors. Here, we revealed that the liver-specific putative lncRNA, AC115619, is expressed at low levels in hepatocellular carcinoma (HCC) and encodes a micropeptide, designated as AC115619-22aa. AC115619 played a crucial role in the regulation of tumor progression and was a prognostic indicator in HCC. The encoded micropeptide AC115619-22aa inhibited the progression of HCC by binding to WTAP and impeding the assembly of the N6-methyladenosine (m6A) methyltransferase complex, which regulates the expression of tumor-associated genes, such as SOCS2 and ATG14. AC115619 was cotranscribed with the adjacent upstream coding gene APOB, and hypoxia induced transcriptional repression of both APOB and AC115619 by controlling HIF1A/HDAC3 and HNF4A signaling. In animal and patient-derived models, AC115619-22aa reduced global m6A levels and suppressed tumor growth. In conclusion, this study establishes AC115619 and its encoded micropeptide as potential prognostic markers and therapeutic targets for patients with HCC.A micropeptide encoded by lncRNA AC115619 impedes formation of the m6A methylation complex to lower m6A levels and reduce the growth of hepatocellular carcinoma.
Facts and Hopes in Colorectal Cancer Immunotherapy
Authors: Michael B. Foote, Guillem Argilés, Benoit Rousseau, Neil H. Segal
Journal: Clinical Cancer Research (2023)

Abstract Although a minority of colorectal cancers exhibit mismatch repair deficiency and associated sensitivity to immune checkpoint inhibitors (ICI), the vast majority of colorectal cancers arise in a tolerogenic microenvironment with mismatch repair proficiency, low tumor-intrinsic immunogenicity, and negligible immunotherapy responsiveness. Treatment strategies to augment tumor immunity with combination ICIs and chemotherapy have broadly failed in mismatch repair–proficient tumors. Similarly, although several small single-arm studies have shown that checkpoint blockade plus radiation or select tyrosine kinase inhibition may show improved outcomes compared with historical controls, this finding has not been clearly validated in randomized trials. An evolving next generation of intelligently engineered checkpoint inhibitors, bispecific T-cell engagers, and emerging CAR-T cell therapies may improve immunorecognition of colorectal tumors. Across these modalities, ongoing translational efforts to better define patient populations and biomarkers associated with immune response, as well as combine biologically sound and mutually amplifying therapies, show promise for a new era of immunotherapy in colorectal cancer.
Do Prolonged Infusions of β-Lactam Antibiotics Improve Outcomes in Critically Ill Patients With Sepsis?
Authors: Claire N. Shappell, Michael Klompas, Chanu Rhee
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Experiences of US Clinicians Contending With Health Care Resource Scarcity During the COVID-19 Pandemic, December 2020 to December 2021
Authors: Catherine R. Butler, Aaron G. Wightman, Janelle S. Taylor, John L. Hick, Ann M. O’Hare
Journal: JAMA Network Open (2023)

Importance The second year of the COVID-19 pandemic saw periods of dire health care resource limitations in the US, sometimes prompting official declarations of crisis, but little is known about how these conditions were experienced by frontline clinicians. Objective To describe the experiences of US clinicians practicing under conditions of extreme resource limitation during the second year of the pandemic. Design, Setting, and Participants This qualitative inductive thematic analysis was based on interviews with physicians and nurses providing direct patient care at US health care institutions during the COVID-19 pandemic. Interviews were conducted between December 28, 2020, and December 9, 2021. Exposure Crisis conditions as reflected by official state declarations and/or media reports. Main Outcomes and Measures Clinicians’ experiences as obtained through interviews. Results Interviews with 23 clinicians (21 physicians and 2 nurses) who were practicing in California, Idaho, Minnesota, or Texas were included. Of the 23 total participants, 21 responded to a background survey to assess participant demographics; among these individuals, the mean (SD) age was 49 (7.3) years, 12 (57.1%) were men, and 18 (85.7%) self-identified as White. Three themes emerged in qualitative analysis. The first theme describes isolation. Clinicians had a limited view on what was happening outside their immediate practice setting and perceived a disconnect between official messaging about crisis conditions and their own experience. In the absence of overarching system-level support, responsibility for making challenging decisions about how to adapt practices and allocate resources often fell to frontline clinicians. The second theme describes in-the-moment decision-making. Formal crisis declarations did little to guide how resources were allocated in clinical practice. Clinicians adapted practice by drawing on their clinical judgment but described feeling ill equipped to handle some of the operationally and ethically complex situations that fell to them. The third theme describes waning motivation. As the pandemic persisted, the strong sense of mission, duty, and purpose that had fueled extraordinary efforts earlier in the pandemic was eroded by unsatisfying clinical roles, misalignment between clinicians’ own values and institutional goals, more distant relationships with patients, and moral distress. Conclusions and Relevance The findings of this qualitative study suggest that institutional plans to protect frontline clinicians from the responsibility for allocating scarce resources may be unworkable, especially in a state of chronic crisis. Efforts are needed to directly integrate frontline clinicians into institutional emergency responses and support them in ways that reflect the complex and dynamic realities of health care resource limitation.
Uncovering the Genomic Basis of Infection Through Co-genomic Sequencing of Hosts and Parasites
Authors: Eric Dexter, Peter D Fields, Dieter Ebert
Journal: Molecular Biology and Evolution (2023)

Understanding the genomic basis of infectious disease is a fundamental objective in co-evolutionary theory with relevance to healthcare, agriculture, and epidemiology. Models of host-parasite co-evolution often assume that infection requires specific combinations of host and parasite genotypes. Co-evolving host and parasite loci are, therefore, expected to show associations that reflect an underlying infection/resistance allele matrix, yet little evidence for such genome-to-genome interactions has been observed among natural populations. We conducted a study to search for this genomic signature across 258 linked host (Daphnia magna) and parasite (Pasteuria ramosa) genomes. Our results show a clear signal of genomic association between multiple epistatically interacting loci in the host genome, and a family of genes encoding for collagen-like protein in the parasite genome. These findings are supported by laboratory-based infection trials, which show strong correspondence between phenotype and genotype at the identified loci. Our study provides clear genomic evidence of antagonistic co-evolution among wild populations.
A Multifunctional Nanozyme with NADH Dehydrogenase‐Like Activity and Nitric Oxide Release under Near‐Infrared Light Irradiation as an Efficient Therapeutic for Antimicrobial Resistance Infection and Wound Healing
Authors: Yi Wang, Hong‐dong Shi, Hai‐Lin Zhang, Yu‐ Yu Chen, Bing Ren, Qi Tang, Qi Sun, Qian‐Ling Zhang, Jin‐Gang Liu
Journal: Advanced Healthcare Materials (2023)

In recent years, antimicrobial resistance (AMR) has become one of the greatest threats to human health. There is an urgent need to develop new antibacterial agents to effectively treat AMR infection. Herein, a novel nanozyme platform (Cu,N-GQDs@Ru-NO) is prepared, where Cu,N-doped graphene quantum dots (Cu,N-GQDs) are covalently functionalized with a nitric oxide (NO) donor, ruthenium nitrosyl (Ru-NO). Under 808 nm near-infrared (NIR) light irradiation, Cu,N-GQDs@Ru-NO demonstrates nicotinamide adenine dinucleotide (NADH) dehydrogenase-like activity for photo-oxidizing NADH to NAD+ , thus disrupting the redox balance in bacterial cells and resulting in bacterial death; meanwhile, the onsite NIR light-delivered NO effectively eradicates the methicillin-resistant Staphylococcus aureus (MRSA) bacterial and biofilms, and promotes wound healing; furthermore, the nanozyme shows excellent photothermal effect that enhances the antibacterial efficacy as well. With the combination of NADH dehydrogenase activity, photothermal therapy, and NO gas therapy, the Cu,N-GQDs@Ru-NO nanozyme displays both in vitro and in vivo excellent efficacy for MRSA infection and biofilm eradication, which provides a new therapeutic modality for effectively treating MRSA inflammatory wounds.